EUROPEAN UROLOGY 65 (2014) 979–980
available at www.sciencedirect.com journal homepage: www.europeanurology.com
Platinum Priority – Editorial Referring to the article published on pp. 968–978 of this issue
Do Erectile Dysfunction and Cardiovascular Disease Have the Same Mechanism? Hillary A. Keenan * Section of Vascular Cell Biology, Joslin Diabetes Center, Harvard Medical School, One Joslin Place, Boston, MA 02215, USA
Erectile dysfunction (ED) is important for both affecting quality of life and being a possible harbinger of cardiovascular disease (CVD) [1–3]. Epidemiological and clinical data on the role of risk factors in vascular dysfunction in the natural history of both ED and CVD are summarized in this month’s European Urology by Gandaglia et al. [4]. This review summarizes the evidence for a linkage between the two clinical presentations; the paper also highlights key questions yet to be answered. Most practitioners would agree that the connection between these two conditions should be exploited as a screening tool, as Gandaglia et al. and others have suggested; however, the relationship of the two clinical presentations and their underlying causes may be confounded by coexisting metabolic milieus, with the most common the metabolic syndrome [1,3,5]. While men may be unaware of, or unwilling to address, other cardiovascular risk factors such as being overweight, ED is a likely motivator for a visit to the gym or even the physician. In 2005, Ganz clearly described the disruption of nitric oxide activation that leads to the vasodilation essential for erection and is part of regular cardiac function [6]. Successful treatment of ED with phosphodiesterase type 5 (PDE5) inhibitors, which prevent the breakdown of cyclic guanosine monophosphate, provides empirical evidence of its importance in the endothelial dysfunction leading to ED [6]. However, its role in CVD has not been as clear; current trials of sildenafil do not show convincing evidence for its use in the treatment of congestive heart failure. Several epidemiological studies have shown few links between PDE5 inhibitor use and the occurrence of cardiac events [7,8]. This situation suggests different responses to risk factors on a tissuespecific level, analogous to the effects of hyperglycemia on the development of microvascular complications in diabetes; some patients may develop retinopathy but not nephropa-
thy, and vice versa, despite exposure to the same risk factors [9]. Tissue-specific sensitivities, of course, are difficult to assess in large epidemiological studies. Recent studies attempt to narrow down risk factors and speculate on pathways that contribute to increased risk for ED and/or CVD—including body mass index, androgen deficiency, dyslipidemia, inflammatory markers, smoking, diabetes, age, medications, hypertension, and psychosocial factors— by examining the use of pharmaceutical therapies. Looking at the identified risk factors in aggregate, with the exception of psychosocial factors, there is tremendous overlap with the metabolic/insulin resistance syndrome and associated factors, which can precede both ED and CVD by several years [10]. In a recent paper, Gandaglia et al. support components of this hypothesis in their review of the evidence for CVD and diabetes mellitus [3]. This metabolic milieu—components of which often work synergistically to accelerate pathogenic effects on endothelial cells, likely contributing to ED even before clinical diabetes mellitus— may serve as a marker of the onset of silent CVD or an impending CVD event well in advance of the 2–3 yr that ED might [5]. A review of the literature including these terms may broaden the view from one that considers the biochemical mechanism of ED and CVD to be the same to the view that common risk factors lead to vascular dysfunction, but the molecular mechanism may vary on the tissue-specific level; the latter view addresses the question of why there is not a one-to-one relationship between ED and CVD development. The review in this month’s European Urology by Gandaglia et al. touches on many salient points of the relationship between ED and CVD: common risk factors and a common serial presentation [4]. Two takeaway messages result from this paper: (1) Self-awareness of risk factors (with fat mass as
DOI of original article: http://dx.doi.org/10.1016/j.eururo.2013.08.023. * Tel. +1 617 309 3421; Fax: +1 617 309 3483. E-mail address: [email protected]. 0302-2838/$ – see back matter # 2013 European Association of Urology. Published by Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.eururo.2013.11.013
980
EUROPEAN UROLOGY 65 (2014) 979–980
the most important and addressable risk factor) is crucial, and (2) as we experience a paradigm shift to translational medicine, it will be important to understand how the effects of these common risk factors function on the biochemical level to determine the best course of care. Conflicts of interest: The author has nothing to disclose.
[5] D’Agostino Sr RB, Grundy S, Sullivan LM, Wilson P, CHD Risk Prediction Group. Validation of the Framingham coronary heart disease prediction scores: results of a multiple ethnic groups investigation. JAMA 2001;286:180–7. [6] Ganz P. Erectile dysfunction: pathophysiologic mechanisms pointing to underlying cardiovascular disease. Am J Cardiol 2005;96: 8M–12M. [7] Amin A, Mahmoudi E, Navid H, Chitsazan M. Is chronic sildenafil
References
therapy safe and clinically beneficial in patients with systolic heart failure? Congest Heart Fail 2013;19:99–103.
[1] Araujo AB, Hall SA, Ganz P, et al. Does erectile dysfunction contrib-
[8] Mittleman MA, Maclure M, Lewis MA, et al. Cardiovascular out-
ute to cardiovascular disease risk prediction beyond the Framing-
comes among sildenafil users: results of the International Men’s
ham risk score? J Am Coll Cardiol 2010;55:350–6.
Health Study. Int J Clin Pract 2008;62:367–73.
[2] Inman BA, Sauver JL, Jacobson DJ, et al. A population-based, longi-
[9] Sun JK, Keenan HA, Cavallerano JD, et al. Protection from retinopa-
tudinal study of erectile dysfunction and future coronary artery
thy and other complications in patients with type 1 diabetes of
disease. Mayo Clin Proc 2009;84:108–13.
extreme duration: the Joslin 50-year medalist study. Diabetes Care
[3] Gandaglia G, Salonia A, Passoni N, Montorsi P, Briganti A, Montorsi F. Erectile dysfunction as a cardiovascular risk factor in patients with diabetes. Endocrine 2013;43:285–92.
2011;34:968–74. [10] Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Executive summary of the third report of the
[4] Gandaglia G, Briganti A, Jackson G, et al. A systematic review of
National Cholesterol Education Program (NCEP) Expert Panel on
the association between erectile dysfunction and cardiovascular
Detection, Evaluation, and Treatment of High Blood Cholesterol in
disease. Eur Urol 2014;65:968–78.
Adults (Adult Treatment Panel III). JAMA 2001;285:2486–97.
available at www.sciencedirect.com journal homepage: www.europeanurology.com
Platinum Priority – Editorial Referring to the article published on pp. 968–978 of this issue
Do Erectile Dysfunction and Cardiovascular Disease Have the Same Mechanism? Hillary A. Keenan * Section of Vascular Cell Biology, Joslin Diabetes Center, Harvard Medical School, One Joslin Place, Boston, MA 02215, USA
Erectile dysfunction (ED) is important for both affecting quality of life and being a possible harbinger of cardiovascular disease (CVD) [1–3]. Epidemiological and clinical data on the role of risk factors in vascular dysfunction in the natural history of both ED and CVD are summarized in this month’s European Urology by Gandaglia et al. [4]. This review summarizes the evidence for a linkage between the two clinical presentations; the paper also highlights key questions yet to be answered. Most practitioners would agree that the connection between these two conditions should be exploited as a screening tool, as Gandaglia et al. and others have suggested; however, the relationship of the two clinical presentations and their underlying causes may be confounded by coexisting metabolic milieus, with the most common the metabolic syndrome [1,3,5]. While men may be unaware of, or unwilling to address, other cardiovascular risk factors such as being overweight, ED is a likely motivator for a visit to the gym or even the physician. In 2005, Ganz clearly described the disruption of nitric oxide activation that leads to the vasodilation essential for erection and is part of regular cardiac function [6]. Successful treatment of ED with phosphodiesterase type 5 (PDE5) inhibitors, which prevent the breakdown of cyclic guanosine monophosphate, provides empirical evidence of its importance in the endothelial dysfunction leading to ED [6]. However, its role in CVD has not been as clear; current trials of sildenafil do not show convincing evidence for its use in the treatment of congestive heart failure. Several epidemiological studies have shown few links between PDE5 inhibitor use and the occurrence of cardiac events [7,8]. This situation suggests different responses to risk factors on a tissuespecific level, analogous to the effects of hyperglycemia on the development of microvascular complications in diabetes; some patients may develop retinopathy but not nephropa-
thy, and vice versa, despite exposure to the same risk factors [9]. Tissue-specific sensitivities, of course, are difficult to assess in large epidemiological studies. Recent studies attempt to narrow down risk factors and speculate on pathways that contribute to increased risk for ED and/or CVD—including body mass index, androgen deficiency, dyslipidemia, inflammatory markers, smoking, diabetes, age, medications, hypertension, and psychosocial factors— by examining the use of pharmaceutical therapies. Looking at the identified risk factors in aggregate, with the exception of psychosocial factors, there is tremendous overlap with the metabolic/insulin resistance syndrome and associated factors, which can precede both ED and CVD by several years [10]. In a recent paper, Gandaglia et al. support components of this hypothesis in their review of the evidence for CVD and diabetes mellitus [3]. This metabolic milieu—components of which often work synergistically to accelerate pathogenic effects on endothelial cells, likely contributing to ED even before clinical diabetes mellitus— may serve as a marker of the onset of silent CVD or an impending CVD event well in advance of the 2–3 yr that ED might [5]. A review of the literature including these terms may broaden the view from one that considers the biochemical mechanism of ED and CVD to be the same to the view that common risk factors lead to vascular dysfunction, but the molecular mechanism may vary on the tissue-specific level; the latter view addresses the question of why there is not a one-to-one relationship between ED and CVD development. The review in this month’s European Urology by Gandaglia et al. touches on many salient points of the relationship between ED and CVD: common risk factors and a common serial presentation [4]. Two takeaway messages result from this paper: (1) Self-awareness of risk factors (with fat mass as
DOI of original article: http://dx.doi.org/10.1016/j.eururo.2013.08.023. * Tel. +1 617 309 3421; Fax: +1 617 309 3483. E-mail address: [email protected]. 0302-2838/$ – see back matter # 2013 European Association of Urology. Published by Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.eururo.2013.11.013
980
EUROPEAN UROLOGY 65 (2014) 979–980
the most important and addressable risk factor) is crucial, and (2) as we experience a paradigm shift to translational medicine, it will be important to understand how the effects of these common risk factors function on the biochemical level to determine the best course of care. Conflicts of interest: The author has nothing to disclose.
[5] D’Agostino Sr RB, Grundy S, Sullivan LM, Wilson P, CHD Risk Prediction Group. Validation of the Framingham coronary heart disease prediction scores: results of a multiple ethnic groups investigation. JAMA 2001;286:180–7. [6] Ganz P. Erectile dysfunction: pathophysiologic mechanisms pointing to underlying cardiovascular disease. Am J Cardiol 2005;96: 8M–12M. [7] Amin A, Mahmoudi E, Navid H, Chitsazan M. Is chronic sildenafil
References
therapy safe and clinically beneficial in patients with systolic heart failure? Congest Heart Fail 2013;19:99–103.
[1] Araujo AB, Hall SA, Ganz P, et al. Does erectile dysfunction contrib-
[8] Mittleman MA, Maclure M, Lewis MA, et al. Cardiovascular out-
ute to cardiovascular disease risk prediction beyond the Framing-
comes among sildenafil users: results of the International Men’s
ham risk score? J Am Coll Cardiol 2010;55:350–6.
Health Study. Int J Clin Pract 2008;62:367–73.
[2] Inman BA, Sauver JL, Jacobson DJ, et al. A population-based, longi-
[9] Sun JK, Keenan HA, Cavallerano JD, et al. Protection from retinopa-
tudinal study of erectile dysfunction and future coronary artery
thy and other complications in patients with type 1 diabetes of
disease. Mayo Clin Proc 2009;84:108–13.
extreme duration: the Joslin 50-year medalist study. Diabetes Care
[3] Gandaglia G, Salonia A, Passoni N, Montorsi P, Briganti A, Montorsi F. Erectile dysfunction as a cardiovascular risk factor in patients with diabetes. Endocrine 2013;43:285–92.
2011;34:968–74. [10] Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Executive summary of the third report of the
[4] Gandaglia G, Briganti A, Jackson G, et al. A systematic review of
National Cholesterol Education Program (NCEP) Expert Panel on
the association between erectile dysfunction and cardiovascular
Detection, Evaluation, and Treatment of High Blood Cholesterol in
disease. Eur Urol 2014;65:968–78.
Adults (Adult Treatment Panel III). JAMA 2001;285:2486–97.
